JPS6193169A - Pyridazinone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 and R2 are H or lower alkyl; R3 is group of formula II (R is O or S; A is alkylene; R7 is OH, lower alkoxy, etc.), etc.; R4 and R5 are H, lower alkyl, halogen, OH, etc.; R6 is H, lower alkyl, etc.; the bond containing dotted line is single or double] and its salt. EXAMPLE:6-{3-Chloro-4-[N-(2-morpholinoethyl)carbamoylmethoxy]p-henyl}- 4,5-di hydro-3-(2H)pyridazinone. USE:Cardiotonic, antihypertensive agent, and remedy for thrombotic diseases. PREPARATION:The compound of formula I wherein R3 is group of formula II, R4 is R10, R5 is R11, and R6 is H, can be prepared e.g. by converting the compound of formula III (R10 and R11 are R1, R2, halogen, lower alkoxy, etc.) to an alkali metal salt, and reacting the salt with the compound of formula IV (R12 is lower alkoxy, aryloxy, etc.; X is halogen).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyridazinone derivative and a pharmacologically acceptable salt thereof having an inhibitory effect on platelet aggregation, and a method for producing the same.

Conventionally, pyridazinone derivatives substituted with alkoxyphenyl groups have been known as pyridazinone derivatives having cardiotonic effects, antihypertensive effects, etc. (Japanese Unexamined Patent Publication No. 47-18
No. 8114 and Japanese Unexamined Patent Publication No. 58-8015).

The present inventors have conducted intensive studies over many years on the synthesis of novel pyridazinone derivatives and their pharmacological effects, and have determined that these derivatives have excellent long-lasting effects and/or excellent long-lasting effects. The present inventors have completed the present invention by discovering that the compound is an important intermediate for the synthesis of active compounds.

(composition) The novel pyridazinone derivative according to the present invention has -.

In the above formula, R1 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, R and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, R is of the formula -Q-A-COR, group [wherein, Q represents an oxygen atom or a sulfur atom, A represents an alkylene group, and R7 represents a hydroxyl group; a lower alkoxy group; an aryloxy group; an alkyloxy group; or a group of the formula -B-N<R8 [wherein, B represents a single bond or an imino group, R8 and R9 are the same or different and are a hydrogen atom, an alkyl group, an alkyl group having one or two substituents (the substituents are), a rogen atom, a hydroxyl group, a lower alkoxy group, aryloxy group, amino group, mono- or di-substituted amino group, carboxy group, lower alkoxycarbonyl group, cycloalkyl group, heterocyclyl group (indicates an aryl group or heteroaryl group), cycloalkyl group, aryl group or hetero Indicates an aryl group.

Alternatively, R8 and R9 together with the nitrogen atom to which they are attached represent a heterocyclyl group.

Furthermore, the amino group and imino group contained in R8 and R9 may be protected. ]. ], R4 and R5 are the same or different and are a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an aliphatic acyloxy group, an amino group, a mono- or di-lower alkylamino group, represents an aliphatic acylamino group, an aliphatic acyl group, a carboxy group, a lower alkoxy7carbonyl group, a carbamoyl group, a ureido group, a lower alkylureido group, a thioureido group, a lower alkylthioureido group, a cyano group, or a nitro group, and R6 is a hydrogen atom , a lower alkyl group or a substituted lower alkyl group [the substituent is a di-lower alkylamino group, an aryl group, a heterocyclyl group, or a group of the formula -〇〇R, where R7 has the same meaning as described above. ) is shown. ], and bonds with dotted lines indicate single or double bonds.

Definitions and specific examples of terms used for R to R6 in compound (1)K are as follows.

The lower alkyl group or the alkyl moiety of the lower alkoxy group represents a C1-C4 alkyl group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and 8-butyl groups, and are preferably is a methyl or ethyl group.

A represents an alkylene group with C1-06;
For example, methylene, methylmethylene, ethylene, propylene, trimethylene, ethylmethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene,
Mention may be made of 3-methyltrimethylene, pentamethylene, hexamethylene groups, preferably methylene, ethylene, trimethylene or tetramethylene groups.

The aryl group or the aryl moiety of the aryloxy group represents a phenyl or 7-tyl group which may have 1 to 3 substituents, and the substituent is, for example, a lower alkyl group, a lower alkoxy group, a hydroxyl group, or a fluorine group. Examples include halogen atoms such as chlorine, bromine, and iodine, but preferably a phenyl group that may be substituted, and the substituent is methyl, ethyl, methoxy, fluorine atom, or chlorine atom.

The aralkyl group of the aralkyloxy group is, for example, benzyl, p-methylbenzyl, p-7'' loombenzyl, m-chlorobenzyl, p-methoxybenzyl, or phenethyl group.

The unsubstituted or substituted alkyl group of R8, R, is C1-
Indicates an alkyl group of C1o, for example, the above-mentioned 01-04
In addition to the alkyl group, n-pentyl, inhentyl, n
-hexyl, n-hebutyl, n-octyl, n-nonyl, n-decyl, preferably an unsubstituted alkyl group is a C1-08 alkyl group, and a substituted alkyl group In the case of , it is a C4-06 alkyl group. Further, in the case of a substituted alkyl group, a C2-04 alkyl group is more preferable.

The substituent of the mono- or di-substituted amino group is a lower alkyl group or an aryl group, preferably a methyl, ethyl, or phenyl group.

The cycloalkyl group represents a cycloalkyl group of Cs Cy, such as cyclopropyl, 7-clobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and is preferably a cycloalkyl group of Cs C6.

A heterocyclyl group represents a 3- to 7-membered cyclic group containing 1 to 2 oxygen atoms, sulfur atoms, or nitrogen atoms, for example,
Nato-2hydrofuryl, tetrahydropyranyl, tetrahydropyranyl, tetrahydrothioviranyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, hexahydroazepinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, N-substituted pyrazinyl (the substituent is lower alkyl group,
Indicates a phenyl or lower alkoxycarbonyl group that may be substituted.

Preferred are methyl, ethyl, phenyl, methoxycarbonyl, and ethoxycarbonyl groups. ), preferably a 5- or 6-membered cyclic group. In addition, R
The heterocyclyl group represented by 6 and R9 jointly with the nitrogen atom to which they are bonded represents a group containing at least one nitrogen atom among the above-mentioned heterocyclyl groups.

A heteroaryl group is a 5- to 6-membered cyclic aromatic group containing 1 to 2 oxygen atoms, sulfur atoms, or nitrogen atoms, which may be substituted with a lower alkyl group, such as,
Examples include furyl, thiofuryl, 1-methylpyrrolinyl, pyridyl, 2-methylbiridyl, 3-ethylpyridyl, oxazolidyl, thiazolidyl, and pyrimidyl groups, and furyl, thiophryl, and pyridyl groups are preferred.

Examples of the halogeno lower alkyl group include t-fluoro, romether, chloromethyl, dribbleromethyl, 2-chloroethyl, and 4-fluorophthyl groups, and trifluoromethyl group is preferred.

The aliphatic acyl group (including the acyl moiety of an aliphatic acyloxy group or an aliphatic acylamino group) represents an acyl group of CI Cs, such as formyl, acetyl, propionyl, butyl, valeryl, isovaleryl group, and is preferably is an acetyl group.

Examples of the film-retaining group of an amino group or an imino group include an aralkyl group such as benzyl and p-methoxybenzyl, and an aralkyloxycarbonyl group such as benzyloxycarbonyl and p-bromobenzyloxycarbonyl.

Among the compounds having general formula (1) t- of the present invention, the basic compound can be converted into a pharmacologically acceptable conjugate addition salt form, if necessary. Such acid addition salts mean salts with green acids that do not increase the toxicity of basic compounds; examples of these acid addition salts include hydrochloric acid, hydrobromic acid,
Mineral acids such as iodic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid, as well as acetic acid, silicic acid, tartaric acid, citric acid,
Benzoic acid, glycolic acid, gluconic acid, glucuronic acid,
Mention may be made of salts of organic acids such as succinic acid, maleic acid and fumaric acid.

Further, in compound (I), compounds in which [11R, is a hydrogen atom, compounds in which (21Q (in R3)] is an oxygen atom, +
3) R, alkoxy r'9 (in R3) of 01-04 is an imino group, R and R2 are the same or different, a hydrogen atom, a C1Ca alkyl group, a substituted 0 1C6
alkyl group (the substituents are halokene, hydroxyl 4, Cl-0
4 alkoxy group, optionally substituted phenoxy group, amino group, mono- or di-C-C alkylamino group, C
4-04 alkoxycarbonyl group, a 5- to 6-membered cyclic heterocyclyl group, an aryl group, or a 5- to 6-membered cyclic heteroaryl group. ), an optionally substituted phenyl group, Cs C, s cycloalkyl group, and R
and R9 together with the nitrogen atom represents a 5- to 6-membered cyclic heterocyclyl group. ], +4) A compound where E (in R3) is a single bond, (5
) R and R5 are the same or different, hydrogen atom, C1-C
4 alkyl group, halogen atom, trifluoromethyl group, C1-04 alkoxy group, acetyl group, carbazoyl group 1, cyano group or nitro group, (6) R is a hydrogen atom, C4-C4 an alkyl group or a substituted C, C4 alkyl group [the substituent is a di-C1-04 alkylamino group, a phenyl group or a -COR group (in the formula, R
7 is a C1-C4 alkylamino group R14 with a C1=C4 alkoxy group or a 5- to 6-membered cyclic heterocyclyl group. ). ], +7J A compound in which R3 is substituted at the 4-position of the phenyl group, (8) R is a hydrogen atom, and R2 is a hydrogen atom or C-C
is an alkyl group of the formula -〇-A-COR group [wherein A is an alkylene group of 01-04, and R7 is a C1
-04 alkoxy group or formula -B-N<”・group [in the formula,
B is a single bond or an imino group, and R8 and R9 are the same or different and are a hydrogen atom, a C4-C8 alkyl group, a substituted C1-06 alkyl group (the substituent is a halogen,
Hydroxyl group, C1-04 alkoxy group, amino group, mono- or di-C4-C4 alkylamino group, C1-C4 alkoxycarbonyl group, 5- to 6-membered cyclic heterocyclyl group containing a nitrogen atom, optionally substituted phenyl group or a 5- to 6-membered cyclic heteroaryl group. ), an optionally substituted phenyl group or a Cs C6 cycloalkyl group. Further, R and R9 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocyclyl group. ]. ], R and R5 are the same or different and are a hydrogen atom, a C, -C4 alkyl group, a norogen atom, an acetyl group, a trifluoromethyl group, a carbamoyl group, a cyano group, or a nitro group, and R6 is a hydrogen atom, C
-C alkyl group or C4-C4 alkyl group substituted with C, -04 alkylamino or phenyl, (9) R is a hydrogen atom, R2 is a hydrogen atom, a methyl group or an ethyl group; Yes, R3 is a phenyl group C4
-〇-A-COR, group substituted at the position [wherein A is a linear C4-04 alkylene group, R, U C1
-04 alkoxy group or formula is hydrogen atom, C1-0
8 alkyl group or a substituted C4-06 alkyl group (the substituent is a halogen atom, a C-C alkoxy group, a di-C1-C4 alkylamino group, a 5- to 6-membered cyclic group containing a nitrogen atom, is a heterocyclyl group, an optionally substituted phenyl group, or a pyridyl group bonded through a nitrogen atom). ]. ], R4 is a hydrogen atom, R5 is a hydrogen atom substituted at the 3-position of a phenyl group or a methyl group, and R6 is a hydrogen atom.

Examples of the compounds having the general formula (1) obtained by the present invention include the compounds listed in Table 1-5 below.

Table 1 1 HH4-O-CH2Co2B.

1//Me If 3 # H4-04-0-CH2Co2B I
I I 4-O-CI(CONHEt 5 1 1 4-0-0M2CONHPr4-0
-C# Me〃 7 p # 4-o-cH2coNapr(
i) g p tr 4-0-CH2C4-0-
CH2COtr H4-O-CFI C0NH/'VO
Me10 ff 4-OCH2CONHNOEt
11 HH2-OCHC0NH~ O]1iit1
2 tr Me 4-OCHC0N
H/\/\OMe13 /F H4-OCHC
0NH Hadazo 0Fit15 tt tt 4→C
H2C0NH% <]161f/14→CHC'ONH
/'-'N O2 17 II #2-OCFiCONH/'-'N.

XJ 21 /l // 4-OCH2CONH
~1S22 /J 〃4-OCH2CONHNHf
'J'N,,023 tt tt 44-0
-CC0NHI024 HMe 4-0-CHC
0NH/'%/■25 # H4-o-aH2c
, oN4ne26 # # 44-0CJCO
NH40@29 1 Me
#30 # H4-oCH2CONH5
32ps 4-OCHcONH8G34
HJ → C) f C0N) I〃Blade 35 # # 4-
clCH2CONH2 Halo R1-He R5-R6-H Table 2 36 4-O-OH2Co2111
3-C13744-0CH2Co2゜38 4-00H20021%,
2-Cl39
5-at40
3-M@41
3-OM.

42 3-N
o243 4-8C! 1 for H2Co2;
3-C1454-OCFi20H2Co2Et 46 4-04G(29C02111; 2t 47 4-OCHOO21t 48 4-0(-01(2+4-Co2E1;
3-ate 49 4-O-OHCH20H2C! 0211;
#50 4-0 (H2Co□Pr(11)5
1 4-OCH2Cl 02 Bu(n)52 4-
00H2Co2 barrel 53 4-0 to OCH2Co2 54 4-QC! HCONHNH2 554-00H20ONH2 5644-00H2CONH.

e 57 4-00H (!ONHM.

t 58 4-Of: HC! ONHM.

59 4-OCjH20ONHI5t60
3-F'6
1 4-0120ONHNHEt 3-C
1624-OCH20ONHPr(n) 63 4-00H2CjONHPr<1 no 54
#
3-FMθ 65 4-00HCONHPr (n)
3-C1664-OCHCONHPr(n)
3-C1674-00H2 (!0NHB
u(n) -684-00H20ONHBu
(1) 69 4-OCH2CONH, melt (θ) 70
4-00H20ONHO5H1, (p>
171 4-00H20H20ONHO5H,, (n
) t72 4-OCR20H20ONHO
6H,, (n) 173
2-F74 4
-00H20ONHC,H,5(n) 3-
C1754-00H2(!0NHC!8H1,(n)e 76 4-00H20ON(e 77 4-OCR20ON<” t jiii; 79 4-ocm2coN, (”” Pr(n) 80 4-00H20ON<” Bu(n) 84 4-001112CONHA/F85 4-
00H20ONHA/C186400H2CONH/V
Br 87 4-00H20ONH/'-△C1884-o
C'H2O0NH/VOH 894-OCH2Cl ONHNOM6 2-
Cl90
3-C1913-MO S2 4-OCH2CONH/VOEt2-0193

3-C! ! 94
3-Fe2
3-Br96
a-
MOS 97 3-N
H-CNH298 2 00H20ONH/VoEt
3 CIMe 99 4-OCHOONHA10Ete 100 4-00H2CON◇\0Eit101,
4-OCH20H20ONHNOXt#102 4-
OCH20ONHhaq\OEte 103 <-ocg2coNH/1Vont1j14
4-00H20ONHNOP r(n)
2- F2O34-0(:!H2C!'0F to ONH△
r(n) 3-at106 4-OCH2C!
ONH~0@107 4-00H20ONHA/NH
21084-00H20ONHA/NHMe
'109 4-00H20ONH~NHE1;1
10 4-4-00H2 (30/VN 011174~
OCROOMHACo□■ 118 4-OCH20ONFiA002Xt#12
2 4-0(H2(!ONHha< s -Br
123 4-0(H2GONH/'□ 3-C11
244-0(:!H2O0NHHare0125 4-0(
3H2COru~Q 126 1
3-F127 4-oaH2coHHtSoND
5-at128 4-ocH2coNH~o
5-at129
2-p130 4-00H20ONHA
-/Q 2-01131
3-(7B132
2-Br133
3-M.

134 3- CO
NH2135# 3-0
M.

136 3-NH2
1373-No□ 138
3-(3N139
3-OF3140 2-ocHcoNH~f)
5-at145 4-OCR2C! 0NHAA
10 3-C11464-0(CH2-0ONH/X
/U, It 147 4-OCR2C! ON, Q 148 4-0 hate 22 C0NH/'-10#149
4-O-((H□+(jONHΔdaOI4゜150 4-00HC0NHA10 1514-OCH2CONH/'V''-n152 4-
OCHC30HHN'j”-Mo153 4-QC!H
CONH/'V'Q(101544-0(!Ei2C!
0NHNQ-a)2F″t155 4-00H2CjO
NH△■ 156 44-00H2CO to 157 4-00H20ONH+li! , #
158 40 CH20ONH+cz #15
9 4-0(!H2O0NHbe)ooMe'162 4
-0CR2(E2CONH”””LikeX□M.

163 4-00H2COIJH+C! 1164 4-
oaH2aoNgheha◇z-atf 65
3-Cl166
3-Br167
2-F'168
3-F169
2-M.

170 a-M.

1T13-yo 172 3-OK.

1γ3 3-NH2174
3-NHCOM.

175 3-0ONH217
63-COM.

+77 3-Nl(OONH
21182-0 (A120ONHJ 3-C1
1794-8-cH20ONHH 1sa 4-o-cH2cowHNH△shi■182
4-00H2 (AI2CONH Han■184 4-oc
a2couH4Me 185 4-00H2CONH/”<a) OF186
4-0 (!H2C!oNH40/>a14-oaH2
coNH,,-,2J1sa 4-00H20ONH
+OM+92-at1B9
,c.

190 3-Er191
3-Fi92
3-M8193
3-0M.

1943-cN 195 4-00H2C, ONH Hate oMe3-N
HOOM.

tss 4-oca2coua40Et 5-a
t2003-c! 201 3-Br2G2
2-1203
3-11+204
,M.

2053～Ei 206 3-0M.

20? 3-NH-0-
NHM62013 3-No.
22H3-0N 210 3-OF3213
4-oca2an2coNaJo4 z-at216
400H2C0NK 9 3- C12174-
00H20ONH△bar (D轡218 4-0HC0MM△0 219 4-8-0H2C!ONH/ν■220 4-
4-0-CH2 (A12COha4221 4-00H2
0ONH△△Xkanari224 4-oaH2coNH! Sound 225 4-00H20ONH△0 226 4-00H20ONH△O 2274-QC! H20ONHi 228 4-00H20ONH? 3-at2
29 4-QCH20ONH to 9 230 4-OC! H2C! ONH+2C
12313-C1 2322-Br 233 4-00H2Co)tH△n◇ 3-B
.

234
2-F235
3-F236
3-M.

237 2-0F
323111
3-OM.

239 3
- OKl.

240 3-No2
241
3-NHOOM8242
3-0ONH22433-NHcSNH2 2444-OCjH2CONHNH8ru 3-012
454~S-C! H2O0NH△Reraz46 4-o
-(an2te, C0NHu 3 C12474-00
H2C! Thickness 248 to H2O0NH 4-00H20ON
H heme) Et249 4- OCH20ONH~Ω7θ 250 4-0 fortune HCONH/\, 2be1U〉25
2 4-OCH2CONHIνQ 2-C125
33-C1 2554-0 (H2C!ONH△ba) 256 4-OCH2CONHhehe ■ 257 4- s -0H2coNHJ258 4-0
-CjH20H2CONH~C9259 4-00H0
ONH-mouth 260 4-OCH2CONH→0 261 '4-QCH20ONH-C>
3-C12624-OCH20ONH-C) 263 4-OCH2CONHNH-C>264 4-
00H20ONH ◇ 265 4-00H20ONHNH 2664-OCH20ONH+M.

26t4-00H2CONH■)F 268 4- OCR20ONH+OMθ269 4-
OCH20ONH force 270 4-00H2C! ONH-'¥'271 4-
00H20ONH# 2T24-○0H2f:! ONH sweep 2γ3 4-00H2Co-n7J 274 4-00H2CONH-N,]]2T54-○
ca2co-m'J /'5 276 4-OCHCo-N,,) 3-
O12784-OCH200-υ 280 4-00H2C! O-N”N-■【-ノ281 4-QC!H2Co-υ-Co2Et
□ Akira = R6 = H Table 3 283 HM@-0-CH2Co2Zt2-C12
841113-C1 2B5 M9H 286 MB MB -0-OH2002F
Xt3-C1287j (#-8-OH21:!
02Fft2138 1 #-o-ca2cH2c
o2Et1289 / # -0-0M2C
ONHPr(n>290 MeE -0-(:
! H2O0NHPr(1) #291 H
Me-0-(H2CONHEu(n) '292
# # -0-0M2CONHBu(
1) 293! 18H-0-OH20ONHCj5H
11(n) 1294 HM, -0-O
H20ONH○dH13(n) '295 1
' -0-CH20ONH~OMe #2
96 yLBH 29γ f(Me-0-OH20ONHN”298
# Et 299 MeH 30111-00M 0ONH/V0 303 1/
3-M.

304 4 #
3-C1305HM, -OCj
H2QONH△/υ3− Br306 1 #
3-IJHCOMe3Q
T MB H3-C1 308It' 309 HM8- o 0H2colA7υ311
M, M.

312 Hl-80H2001JvV50
#313 #l -0゜yo. . N.H., V.
, -f).

2 XJ 314 1 1 -o0H2coNH~J-M,,
1sts # # -ocH2aoNa4
2-ct316”
2-M.

317 1 1
3-C1318MeH# 319 HMe-s-am2aoya4320#
# -o-ci2comH△high@z32
1 HMe-QC! H20ONH40M6 2 C1
3221' 3
-01323 Me Hz 325 / / 3-
(:!F.

326” 3-M
.

327 1 1 3-N
HOOMe328 MB HI
3-C13291Me 330 H# -oaa2coNa1332
″ ′2-F 333 1 1
3-C1334#I
3-Me335 # #
3-NHC! OM.

336 MB H3-C1 3371Me 339 MeH-0CH2CONH43-C1340
HMe-OCH2 (3ONH~DR4 3-Ol, R5
Noodle H Table 4 341 HH-0CH2 (!OK1; -
0H2Co□7342 ″ ″
-OH, A■343 1 1 -OCH20ONH~
0Fii ne344 1 Me-00H2
0ONH%fl--] 3451 HIt 3461 M.

347 1 H-aH2-@F-t 348 HH-CH2C0NHA/<3'
-N to ClH2.

349”-0T(2CON
HAv-C350# I -00H2CONH~tsu Mo2S3 ” -OCH2C0NH~〆O
M,, Eit352 #I-00H20
ONH 8Ω -CH2 [with] 353 # t
-oa(2coNH4-am2 to $6-H Table 5 354 HH-00H2Co□F, tz-ct 3
-at355 I 1 1
3-C15-01356# # -O
CH2CONHM, 2-C13-C1357H
H-0CH20ONHPr(nl 2-C13-
0/358' t -00H2CONHA10
H3591R6-0CH20ONH~OE1;
1361 1 # -00H2C! ONH~@
2-at 3-ct362'l
3-C1
5-C1363s z -0a (□C!ON, H+
OMe 2-F 3-at364 1 #
2-C
I l367 1 #
2-Cl 3-C
136811A-C15-Cl1 36B 1 R62-F 3-Br370
1 H-oaa2coNH4371”
2-10/3
-Ct372#'
3-Cl 5-C1
In Table 1-5, "er"t+ Pr and Bu represent a methyl group, an ethyl group, a propyl group, and a butyl group, respectively.

In the compounds shown in Table 1-5, a bond containing a dotted line indicates a single bond or a double bond. The number of the gold compound is indicated by adding a mark c') to the exemplified compound number. Compound (1) according to the present invention can be easily produced according to the method shown below.

Method A OD (Ia) Method B (1) (ff) In the above formula, R1+ R2+ R3+ R4+ R5+
R6+Q+A and combinations containing dots have the same meanings as above, % R,. and R11 are the same or different and are a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, a halogen atom, a lower alkoxy group, an aliphatic acyl group, a substituted amino group, a substituted mono-lower alkylamino group. R12 is Indicates a lower alkoxy group, aryloxy group or aralkyloxy group.

Story A is a method for producing a target compound by modifying a pyridazinone compound.

The first step of method A is a step of producing a compound having the general formula cl&), in which the compound having the general formula (It)? : After converting the compound into an alkali metal salt, -formula% formula% () (in the formula, R12 and A have the same meaning as described above,
X represents a halogen atom such as chlorine, odor, or iodine. ) is achieved by reacting a compound with n.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but preferably amide solvents such as dimethylformamide, dimethylacetamide, and hexamethylphosphoryl triamide; sulfoxides such as dimethyl sulfoxide; Alternatively, nitriles such as acetonitrile can be mentioned.

The alkali metal salt of compound (II) is a combination of compound (la) and an alkali metal compound, for example, an alkali metal hydride such as sodium hydride, potassium hydride, or inbutylcyclohexylaminolithium, dicyclohexylaminolithium. an organolithium compound such as O, -20
It is produced by processing for 30 minutes to 2 hours at °C to room temperature.

The reaction between the alkali metal salt of compound (Ia) and compound (V) is carried out in the reaction solution after the alkali metal salt has been left behind. The time required is 30 minutes to 5 hours.

In this step, compound (V) was used in excess.
By increasing the reaction conditions, it is also possible to simultaneously introduce the formula -A-(3OR42 group (wherein A and R12 are the same as D and 0 as described above) into the imino group at the 2-position.

After the reaction is completed, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after distilling off the solvent from the reaction mixture, adding ice water and extracting with water-immiscible M solvent,
It can be obtained by washing the extract with water, drying, and then distilling off the solvent. Further, if necessary, the usual method, e.g.
It can also be purified by recrystallization, column chromatography, etc.).

Note that the raw material compound (1) in this step is either known or prepared using a known method, for example, Journal of Methynal Chemistry, Vol. 17.

213 pages (1974) [J, Med, C! hem
, 17, 273 (1974)] or a method similar to the third to fourth steps of method B.

The second step is a step carried out as desired, in which compound (Ia) is subjected to the reaction shown below to produce compound CI).

The reaction in this step is a reaction of hydrolyzing an ester moiety (aliphatic acyloxy7 group, lower alkoxycarbonyl group, aryloxycarbonyl group, or aralkyloxycarbonyl group), carboxyl group, lower alkoxy, aryloxy, or aralkyloxycarbonyl group. reaction for converting into an optionally substituted hydrazinocarbonyl or carbamoyl group, reaction for converting into a nitro amine group, reaction for converting an amino group into a mono- or di-lower primary alkylamino group, reaction of converting an amino group into an optionally substituted hydrazinocarbonyl or carbamoyl group, reaction of converting an amino group into a mono- or di-lower primary alkylamino group, In the reaction to remove the protecting group, R14 group (in the formula, R14
represents the same group as the above R6D except for the hydrogen atom. ), reactions that convert a carboxy group into an alkoxycarbonyl group, and reactions that convert a bond containing a dotted line into a double bond when it is a single bond, and these reactions may be performed in the appropriate order. The hydrolysis reaction of the ester moiety is carried out according to a conventional method. For example, the corresponding compound is mixed with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an inert solvent such as aqueous ethanol.
This is carried out by treating at a temperature of 100°C to 100°C for 10 minutes to 2 hours.

In the reaction of converting a lower alkoxycarbonyl group etc. into an optionally substituted hydrazinocarbonyl group or carbamoyl group, the corresponding compound is converted into a compound of the general formula % formula % (2) (in the formula, R8e R9 and (B has the same meaning as defined above).

Examples of the inert solvent used include the same solvents as those exemplified in the first step or alcohols such as methanol and ethanol.

The reaction temperature is 0°C to 150°C, and the time required for the reaction is 30 minutes to 24 hours.

The reaction of converting a carboxylic acid into an amide compound involves converting the corresponding compound into a compound (W) in an inert solvent in the presence of a dehydrating agent.
) is achieved by reacting with

Examples of the dehydrating agent used include carbodiimides such as dicyclohexylcarbodiimide, or cyanophosphoric acid esters such as cyanodiethyl phosphoric acid and cyanodimethyl phosphoric acid, but preferably cyanophosphoric acid esters. It is.

The inert solvent used may be the same as in the first step.

Further, the reaction is preferably carried out in the presence of a base, and examples of the base used include triethylamine, pyridine, 4-
Organic amines such as dimethylaminopyridine may be mentioned.

The reaction temperature is 0°C to 50°C, and the time required for the reaction is 2 to 24 hours.

This step can also be achieved by converting the carboxylic acid into a reactive derivative of the carboxylic acid and then reacting it with the compound (l).

Examples of reactive derivatives of carboxylic acids include acid halides such as acid chlorides, acid anhydrides of organic carboxylic acids such as acetic acid, teropionic acid, pivalic acid, and the corresponding carboxylic acids, or inbutoxycarbonyl esters of the corresponding carboxylic acids. The reactive derivatives can be easily prepared by treating the carboxylic acid with a halogen derivative such as thionyl chloride, acetyl chloride, pivaloyl chloride, imbutoxycarbonyl chloride according to the process method. can be obtained.

The reaction is carried out in an inert solvent such as benzene, hydrocarbons such as n-hexane or ethers.

This is carried out by contacting both compounds in an ether such as tetrahydrofuran in the presence of the above-mentioned organic amine at around room temperature for 30 minutes to 3 hours.

The reaction for converting to nitro-based amino groups is carried out in an inert solvent,
This is achieved by treating the corresponding compound with a reducing agent or by catalytic reduction.

Reducing agents used include metals such as zinc, iron, nickel, and tin and organic carboxylic acids such as acetic acid and propionic acid, or stannous chloride and dilute mineral acids such as dilute hydrochloric acid and dilute sulfuric acid. but preferably zinc-acetic acid or zinc chloride
It is tin-dilute hydrochloric acid.

In addition, the inert solvents used include water, methanol,
Examples of alcohols such as ethanol and catalysts used for catalytic reduction include platinum oxide, palladium-black, palladium-carbon, and Raney nickel, and palladium-carbon is preferred. The hydrogen pressure used is from normal pressure to 10 atmospheres, and the inert solvent used is the above-mentioned alcohols, tetrahydrofuran, ethers such as dioxane, the above-mentioned organic carboxylic acids, or a mixed solvent of these organic solvents and water. I can give it to you.

The reaction temperature is 0°C to 50°C, and the time required for the reaction is 30 minutes to 2 hours.

The reaction of converting an amino group into a mono- or di-lower alkylamino group is carried out by converting the corresponding compound in an inert solvent into the general formula % () (wherein, X has the same meaning as above, R1, represents a lower alkyl group).

The reaction is preferably carried out in the presence of a base, and the base used is, for example, a carbonate such as hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate.

Examples of inert solvents used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, alcohols such as methanol and ethanol, water, and mixed solvents of these organic solvents and water. be able to.

The reaction temperature is 0°C to 100°C, and the time required for the reaction is 30 minutes to 5 hours.

In this reaction, by using an almost equivalent amount of the compound (■), the monoalkylamino compound is preferentially produced, and by using an excess amount of the compound (■), the dialkylamino compound is produced preferentially. Manufactured on a priority basis.

The reaction for removing the protective group of an amino group or an imino group is carried out in the same manner as the catalytic reduction reaction when converting a nitro group to an amino group.

The reaction of introducing t-R14 group (R14 has the same meaning as described above) into the imino group at the 2-position is carried out by converting the corresponding compound into an alkali metal salt in an inert solvent, and then converting the general tX-R14 ( [) (wherein, R14 and X have the same meanings as described above.

) This is accomplished by contacting a compound with a

This reaction is carried out in the same manner as the first step.

The reaction for converting a carboxy group into a lower alkoxycarbonyl group is carried out according to a conventional esterification reaction. This is achieved, for example, by reacting the corresponding compound with a diazo lower alkane such as diazomethane, diazoethane, diazopropane in an inert solvent such as ether at around room temperature.

It can also be achieved by reacting the corresponding compound with a lower alcohol such as methanol, ethanol or butanol in the presence of a dehydrating agent. This reaction is carried out in the same manner as the reaction between carboxylic acid and amine.

When the bond containing the dotted line is a single bond, the reaction to convert this bond into a double bond is achieved by halogenating the corresponding compound in an inert solvent and then carrying out a dehydrohalogenation reaction. Ru. Both reactions are carried out in the same reaction solution,
For example, in carboxylic acids such as acetic acid and propionic acid,
This is achieved by treatment with a halogen compound such as chlorine or bromine at 50°C to 150°C for 5 minutes to 1 hour.

After the completion of each of the above reactions, the target compound of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is poured as it is or after distilling off the solvent, poured into ice water, neutralized as desired, extracted with a water-immiscible organic solvent, the extract is washed with water, dried, and then the solvent is distilled off. You can get it by doing this.

Further, if necessary, it can be purified by conventional methods such as recrystallization, column chromatography, etc.

Method B is a method for producing the target compound by introducing a pyridazinone ring moiety into a benzene derivative.

The third step of method B is a step of producing a compound having the general formula fI)' in an inert solvent in the presence of an acid catalyst.
[) in the general formula c, R1a
Bonds including R2 and dotted lines have the same meanings as described above. ).

The acid catalyst used is not particularly limited as long as it is a catalyst used in the Friedel-Crafts reaction, and examples include Lewis acids such as aluminum chloride, zinc chloride, ferric chloride, titanium tetrachloride, poron trifluoride, or hydrogen fluoride. Acids, protons such as sulfuric acid can be mentioned, but aluminum chloride is preferred.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but preferably halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride, or amides such as dimethylformamide and dimethylacetamide. Among them, methylene chloride is preferred.

The reaction temperature is 0°C to 50°C, and the time required for the reaction is 1 to 5 hours.

After completion of the reaction, the target compound of the reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into water-cooled hydrochloric acid, extracting with a water-immiscible organic solvent, washing the extract with water, drying, and then distilling off the solvent.

Furthermore, if necessary, it can be purified by conventional methods such as recrystallization, column chromatography, etc.

The fourth step is a step for producing the entire compound having the general formula (Ib)', and is achieved by contacting the compound having the general formula (IV) t- with hydrazine in an inert solvent.

The solvent used is not particularly limited as long as it does not participate in the reaction, but preferably methanol, ethanol, n
-Alcohols such as propyl alcohol, ethers, ethers such as tetrahydrofuran, water or a mixed solvent of the above organic solvents and water can be used;
Alcohols are preferred.

The reaction temperature is 0°C to 100°C, and the time required for the first reaction is 2 to 10 hours.

After completion of the reaction, the target compound of the reaction is collected from the reaction mixture according to a conventional method. For example, by distilling off the solvent from the reaction mixture, or pouring the reaction mixture into ice water, extracting with a water-immiscible organic solvent, washing the extract with water, drying, and then
It can be obtained by distilling off the solvent. Further, if necessary, it can be purified by conventional methods such as recrystallization, column chromatography, etc.

If converted, the carbonyl moiety can be regenerated by treating the corresponding compound with an acid in an inert solvent.

Examples of the acid used include organic carboxylic acids such as acetic acid and propionic acid, and dilute mineral acids such as dilute hydrochloric acid and dilute sulfuric acid.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but preferably water, alcohols such as methanol and ethanol, hydrous alcohols, ether, and ethers such as dioxane.

The reaction temperature is 20°C to 100°C, and the time required for the reaction is 10 minutes to 3 hours.

The fifth step is a step carried out as desired, and is a step of introducing a formula R14 group (wherein R14 has the same meaning as described above) into the imino group at the 2-position of the compound (l), The reaction is carried out in the same manner as the corresponding reaction in the second step.

(Effect) The compound having the general formula (I) t- is extremely useful as a pharmacological therapeutic agent thereof. The administration form includes, for example, mixing with carrier excipients or diluents such as glucose, sucrose, lactose, sorbitol, starch, polyvinyl, pyrrolidone, mannitol, calcium carbonate, calcium phosphate, sodium chloride, boric acid, etc. Examples include oral administration of powders, granules, tablets, capsules, etc. prepared by the preparation of pharmaceutical preparations, or parenteral administration such as intravenous injection. The dosage varies depending on the target disease, administration method, symptoms, age, body weight, etc., but the withdrawal rate is approximately 0.0 per day for adults.
It can be administered in doses ranging from 0.1 mg to 5089 mg/day, once or in divided doses.

Next, the present invention will be explained in more detail with reference to Test Examples, Examples, and Reference Examples.

Test Example 1゜Inotropic effect on the dog's heart.
Method D [Circulation Researcher f, Volume 45, 66
Page 6 (1979): C1rcul Res
, 45, 668 (1979)), a thin catheter with a built-in pressure sensor at its tip was inserted into the heart through the t-arterial artery, and its tip was placed in the left ventricle, and the resulting pressure waveform was measured. The first derivative value was recorded. The contractile force of the left ventricle was determined from the maximum value.

All test compounds were administered intravenously or intraduodenally as a solution in 0.1N hydrochloric acid or dimethylformamide.

The results obtained are shown in Tables 6 and 7.

Table 6 Inotropic effect due to intravenous administration 93 0.010 54
31131 0.010
59 56200 0.
010 83 67231
D, Djo 71
46 Compound A 0.10 18
15 Amrinone 0.30 21
27 Compound A: 4.5-dihydro-6-(p-methoxyphenyl)-3(2H)-pyridazinone The compound of the present invention shows significant shrinkage compared to the known comparative compound A and commercially available amrinone. It showed an increase in force and the effect was persistent.

Table 1 Cardiac effect 200 by intraduodenal administration
0.1 77231 0.
185 The compound of the present invention exhibits a clear increase in contractile force when administered within 10 times the optimal dose t for intravenous administration, and has the property of being well absorbed from the gastrointestinal tract.

Example 1 6-(3-chloro-4-hydroxyphenyl)-4,
5-dihydro-3(2H)pyridazinone 1, γ9. ? T
Dissolved in 15 ml of dry dimethylformamide and 5 ml of sodium hydride (55%). Add f'ik and stir for 1 hour. To this was added a solution of 1.34 i of ethyl bromoacetate in dimethylformamide under water cooling, and then the mixture was dissolved at room temperature.
Stir for an additional 3 hours at 80°C. After the reaction is complete, dimethylformamide is distilled off under reduced pressure, diluted with water, and extracted with ethyl acetate. The extract was washed with water, dried, concentrated under reduced pressure, and when n-hexane was added, the melting point was 134-136℃.
2H of the target compound as white needle-like crystals with 1.8
5 g was obtained.

Elemental analysis: Calculated value as C14H,5N204C1
C, 54,11; ) I, 4.87; N,
9.01; C1, 11,41 Actual value C, 54,16; H, 4,87: N,
a, 63; Purified with E (elution solvent: ethyl acetate/n-hexane-171) and further recrystallized from ethyl acetate-n-hexane to obtain the target compound 2 as white crystals with a melting point of 146-148°C. -Ethoxycarbonylmethyl form 1.25. I got an F.

Elemental analysis value: c, 6a2. Calculated value as N2o6cz C, 54,48; H, 5,33; N, ? ,0
6; C1, 8,93 Actual value c, 54.27; H, 5,36; N
, y, ol; C1,8,95 Example 2 5 g of 6-(3-/chloro-4-ethoxycarbonylmethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (compound of Example 1), caustic soda zsyt
After stirring at 80° C. for 40 minutes at 50 mf of a 50% ethanol solution containing the mixture, it is cooled and acidified with hydrochloric acid to precipitate crystals. Melting point: 214-21 when recrystallized from aqueous ethanol
Target compound as white crystals with 6 °C &
(73,79%) was obtained.

Elemental analysis value: C,2[(,calculated value as 1N204Ct c, 50.99; a, 3.92;
N, 9,91; C1, 12,54 Actual value C, 51,29; H, 3,92; N,
9.71; C1,12,45 Example 3 (A131) 6-[:3-chloro-4-(carboxymethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (compound of Example 2 ) 0.7.9 and 0.35 g of N-(2-aminoethyl)morpholine were dissolved in dimethylformamide [Itnt, and to this solution was added 5 N ft of trimethylamine o, ss tI and 90 diethyl thicyanophosphate o, under water cooling. . After standing at room temperature for a day and night, the reaction solution was poured into ice water, and the precipitated crystals were recovered from P and recrystallized from ethanol to obtain the target compound (0.611C61.2%) as white crystals with a melting point of 193-194°C. .

Elemental analysis value +8H2gN404 (calculated value as z
C, 54,75; FI, 5.87; N,
14.19; ct, 8.92, actual value 54.59; H, 5,97; N
, 14゜29; 侃, 8.72 Example 4 (Muro 7) 6-[3-/Clo4-(ethoxycarbonylmethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (Example 1 compound) 0.81 and n-butylamine 4- dimethylformamide solution 6d'112
After stirring at 0° C. for 1 hour, the mixture was poured into ice water to collect precipitated crystals. Recrystallization from dimethylformamide gave the target compound 0.6.9 (62.8) as white crystals with a melting point of 14G-141°C.

Elemental analysis value: Calculated value as C,6H2oN503Cl C, 56,89; H, 5,97; N, 12.
44; C1, 10,49 Actual value C, 56,110; H, 6,08; N,
12.34C1,10,56 Example 5 6-[3-chloro-4-(N-(2-morpholinoethyl)carbamoylmethoxy]phenyl)-4,5-dihydro-3(2H)-pyridazinone (Example 4 compound)
Dissolve 1.5, F in acetic acid 18-, and add 1 to this solution.
Acetic acid 2- containing bromine o, as, and v is added dropwise at 00°C. After the dropwise addition was completed, the mixed solution was stirred at the same temperature for 10 minutes, poured into ice water, neutralized with sodium carbonate, and extracted with ethyl acetate. After drying, the extract was concentrated, purified by silica gel column chromatography (elution solvent: ethyl acetate/ethanol-9/1), and further recrystallized from ethanol to obtain white needle-like crystals Q having a melting point of 201-202°C. ,
Obtained 4y (27,0%)9.

Example 6 2-benzyl-6-[3-chloro-4-(ethoxycarbonylmethoxy)phenyl) -4,5CH2ph(4
342) 6-[:3-/Clo4-(ethoxycarbonylmethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone 2.211 (compound of Example 1) was dissolved in dry dimethylformamide 20- , sodium hydride (5
5%) and stirred at room temperature for 3 hours. To this, benzyl bromide 1.44. Add f and stir at 100°C for 4 hours. After the reaction is completed, the mixture is condensed, water is added, and the mixture is extracted with ethyl acetate. The extract was washed with water, dried, reduced, and subjected to silica gel chromatography (developing solvent:
Purified with ethyl acetate/n-hexane-171), melting point 8
The target compound OJOI as white crystals with a temperature of 1-82 °C
(2a, 5ch) was obtained.

Elemental analysis value: Calculated value as C21H2,N204Ct c, 62.92; H, 5,28; N,
6.99; C1, N84 Actual value c, 62J8; H, 5,26; N
, 6.83; ct, a, as Example T 4-[p-(N-n-propylcarbamoylmethoxy)
Phenyl-4-oxobutyric acid (OOC) 40CH2C
ONHCFf2CH2CH5N-n-propylphenoxyacetic acid amide 1.54I and succinic anhydride o,a II
tDissolve methylene chloride 2+)dK. This solution has one temperature ~
After adding 3.36.9 g of anhydrous aluminum chloride little by little at O'C, the mixture was stirred at room temperature for 2 hours. After adding to ice water acidified with hydrochloric acid, extract with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off and the resulting crystals are mixed with methanol.
Reconsolidation with ethyl acetate gave the target compound a, sy as white crystals having a melting point of 122-124°C.

Elemental analysis value C15H1? Calculated value as NO5 C, 6
1,21; H, 6,85; N, 4.76 actual value c, 61.46; H, 6,93; N,
t8a(b) 6-[4-(N-n-propylcarbamoylmethoxy)
phenyl] -4,5-dihydro-3(2H)-pyridazinone onoca2coNac3a7-n 4-[p-(N, -n-propylcarbasoylmethoxy)phenyl-4-oxobutyric acid (compound of Example Tα)
2.3511 and 80% hydrazine 0.33I were dissolved in 40 m of ethanol, refluxed for 5 hours, concentrated, cooled and crystallized to obtain the target compound 1.6I as white crystals with a melting point of 162-165°C. Ta.

Elemental analysis value Calculated value as C15H19N501S c
, 62.27; H, 11,62; N, 1
4.52 Actual value C, 62, j9; H, 6,64;
N, 14.58 The reaction was carried out according to Example 1-7 to obtain the following compound.

I HH4-OCH2CO2Et 126-
128 12tt M@ //
Chant I 5-117
//3 // H4-4-0CH2CON)
I 168-188 4s4 // //
4-OCH2CON plate t168-169 //su6
tl Me 4-OCH2CONHPr(n)
161-1G2 //su7”
” J-OC112CONHPr (1 n 15
0-153 // Ri12 #II
4-OCH2CONH~OMe95-97”R1■R
2 so-called R5-R4■H 384-OCH2CO2Et 2-C1
B5-81 1'0
3-Me 120-121 //4 Snow
'/3
-OMe 142-145 //42
3-NO2154-155/I
M@44 4-OCHCO2Et 3-C
t126-128 //46 4-0 (CH2), C
O21C1II 1&t9-170 1/t 47 4-QC4-0CHCO2911-101/15
4 4-OCH2C'0NHNH21/ 21F
-2194554-OCH7CONH2II 240
-242 IIsu56 4-4-0CH2CONH”
2G! -2054S M・ST 4-OCI'lCO Touche II
11O-11i2 511 4-OCHCONHIJe 3-CL
1711-179 4s82 4-OCH2CON
HPr(n) ” 151-153 ”SB3 4-OCH2CONHPr(1)
# R6-Ra 3e 1is 4-001 (CONFIPr(n)
// l5li-1514 rear 1! 1i 4-OCHcON)iPr(n)
// 1211-130 "su68 4-0(
! H2C0NFrBu (1) 〃14g-1
413H4-OCH2CONHBu(s)
” 155-156 470 4-OCH2C
ON) IC5HB(n) #134-
135 ”t # 173-175 3 114-ocH2°ON(,.

””nts7-tag //lit
4-ocH2°ON (P(n)Bu(n)
, 127-129.82 4-OC'H2C0N
<Bu(n)81 4-OCH2CONH/'y
Act/' 155-157. B93
4-QC)! 2CONH~Out II 16
4-116 4sl Et 114 4-0(:HCONH/AI, /N〈”
ollo) 〃t t B% <<s a-OQHCOyuA, -N< s
oil-), tlt 118 4-OCH20ONH△C02Bt 3
-C11BB -1!0 3127 4-OCH2C
ONH/'yN,] /I 155-157
#1284-OCH2CONR~On 164-18
7 '130 4-OCH,C0NH/'v/N
O2-C1193-1943134t
t3-Me 1g!
-1107'-1373-NOI 202-204
l1146 +beB2u5CONHNHO3
-Cj (ds.,) ″[-ノl5s4-oc[12CONEI αIt //
Hatake) //160 ← Possible 3 CONtf Yes II
172-175 l1165 4-oCH2 Possible V
ν@// 11i5-167 ”189 4-
To OCH2CONH Me 3-cl 1
97-199 31994-OCFI2CONH+e
2-C104-05”200
3-Ct186-1811 11204
3-Me 1
a5-1116 I2011
3-NO21B1-
Goose 63 I216 4-OCH2CONH 5◇
3-Cj! : 15B-11iQ lI217
4-OCH2CONH 8◎ // 1411-
150 11227 4-QC)12CONH1/
l 199-20 snow 4230 4-O
CH2CON+ (Cotton 2-CL 150-1al
3231 3-
Cj 150-1!12 lI240
3-No, 2111
-219 1/2464 Closed HfC0 volume 43-'C11
74-I76 lI261 4-OCH2CONHO”
11i7-1611 I265 4-OCH2CO
NI(N)! @ // 19g-200#21i
8 4-4-0CI(2CONHeO3-CL 196
-1118 3275 4-OCR2CO-01/
119-121 lI279 4-OCH2CO
-N N-M. , 252-253.

Mouth (dec,) 2110 4-OCH2Co-N N-Outas
-tso//li Reacted in ethanol at 10°C for 2 hours.

fist IR spectrum (cuts),
xW' 71675→ l spectrum (CHCjg)
, Sirnaxcm-': 16110(2)-
(b) R5 rope R6m 11 2114 HMe -0-CH2CO2gt
3-cl 13F-13912115Ms
Hpy 15&-157"f-) 304 HMe-0CT42CONH/'V-
N O" 180-162 3-Ino 307 Me H# 15g-167"32
8 Me+ H'/ #13
0-132 “336 // II-0CH
2CON) to IΩ sr 163-164 #(
2) -(c) R4= 3-C4, R5-I 345) I H-0CFi2CONHAV
NOKt 112-1 3 3J 347 // // s -CFi
2@131i"13? "t"44@II # -CH
2^N< 61-85 4t 35G ” ” -0CH2CONHIJf1
"" 2311-239 4') 358
II // -0CH2CONH~O[(II
// 1115-ja7 /1li Reacted in ethanol at 70°C for 2 hours.

R1 R2-R5 skin R4-H I II l' 4-OCH7°. NH9σOMa 3
-CL 21゜-2,2゜Reference Example 1 Dinone 4-(3-/Thyru-4-hydroxyphenyl)-4-oxoacetic acid 24.5, 0-methylaninol of F and 20.0,
f. anhydrous amber M'i 230 mZ was dissolved in dichloromethane. Temperature f of the reaction solution: 84I gold aluminum chloride was gradually added while maintaining the temperature at 5° C. or lower. After the addition, the mixture was stirred at 5° C. or below for 1 hour and then at room temperature for 5 hours. −
After standing for day and night, the reaction mixture was poured into water-cooled diluted hydrochloric acid, and the resulting precipitate was collected. After washing with water, it was dissolved in ethanol, dehydrated by azeotropic distillation, and the solvent was distilled off to obtain 41.6# of the target product as an oily compound.

IR spectrum (liquid) νma1cm': 17
15, 169G(b) 6-(3-)f-4-hydroxyphenyl) -4,
5-dihydroxy-3(2H)-pyridazinone 41.611 carboxylic acid (compound of reference example 1α)
The solution was dissolved in 0.001 nt of ethanol, and 8.21 of 80% hydrazine hydroxide was slowly added dropwise under water cooling. After the dropwise addition, the reaction solution was stirred at the same temperature for 20 minutes and further refluxed for 3 hours. After the reaction solution was left at room temperature for a day and night, it was cooled with ice water, the resulting precipitate was collected and recrystallized from ethanol/ethyl acetate, and the target product having a melting point of 265-267°C was obtained at 22°C.
．． 7, got f.

The following pyridazinone derivatives were obtained in the same manner as in Reference Examples 1a and 1b.

R5-R4-H

Claims (3)

[Claims] (1) Pyridazinone derivatives having the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) and their pharmacologically acceptable salts. In the above formula, R_1 and R_2 are the same or different and represent a hydrogen atom or a lower alkyl group, and R_3 is a group of the formula -Q-A-COR_7 [wherein, Q represents an oxygen atom or a sulfur atom, and A represents an alkylene group] Indicate, R_
7 is a hydroxyl group; a lower alkoxy group; an aryloxy group; an aralkyloxy group; or a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ group [In the formula, B represents a single bond or an imino group (-NH-), R_9 is the same or different and is a hydrogen atom, an alkyl group, an alkyl group having one or two substituents (the substituents are a halogen atom, a hydroxyl group, a lower alkoxy group, an aryloxy group, an amino group, a mono- or di-substituted amino group) , carboxy group, lower alkoxycarbonyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group), cycloalkyl group, aryl group or heteroaryl group. Alternatively, R_8 and R_9 together with the nitrogen atom to which they are attached represent a heterocyclyl group. Furthermore, the amino group and imino group contained in R_8 and/or R_9 may be protected. ]. ], R_4 and R_5 are the same or different and are hydrogen atom, lower alkyl group, halogeno-lower alkyl group, halogen atom, hydroxyl group, lower alkoxy group, aliphatic acyloxy group, amino group, mono- or di-lower alkylamino group, aliphatic group acylamino group, aliphatic acyl group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, ureido group,
A lower alkylureido group, a thioureido group, a lower alkylthioureido group, a cyano group, or a nitro group, and R_6 is a hydrogen atom, a lower alkyl group, or a substituted lower alkyl group [the substituent is a di-lower alkylamino group, an aryl group, It represents a heterocyclyl group or a group of the formula -COR_7 (wherein R_7 has the same meaning as described above). ]
A bond containing a dotted line indicates a single bond or a double bond. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R_1 and R_2 are the same or different and represent a hydrogen atom or a lower alkyl group, R_1_0 and R_1_1 are the same or different and represent a hydrogen atom, Lower alkyl group, halogeno-lower alkyl group, halogen atom, lower alkoxy group, aliphatic acyloxy group, protected amino group, protected mono-lower alkylamino group, di-lower alkylamino group, aliphatic acylamino group, aliphatic acyl group, carboxy group, carbamoyl group, ureido group, lower alkyl ureido group, thioureido group, lower alkyl ureido group, cyano group, or nitro group, Q represents an oxygen atom or a sulfur atom, and the bond containing the dotted line is a single bond or A compound having the general formula represents an alkylene group, and X represents a halogen atom.
_1_2, A, Q, and the combinations containing dotted lines have the same meanings as described above. ), and if desired, hydrolyzed; compound (Ia) or its hydrolysis product (carboxylic acid) and the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) [In the formula, B represents a single bond or an imino group, R_8 and R
_9 is the same or different and is a hydrogen atom, an alkyl group, an alkyl group having one or two substituents (the substituents are a halogen atom, a hydroxyl group, a lower alkoxy group, an aryloxy group,
It represents an amino group, a mono- or di-substituted amino group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group. ), cycloalkyl group, aryl group or heteroaryl group. Alternatively, R_8 and R_9 together with the nitrogen atom represent a heterocyclyl group. Also, R_8 and R
The amino group and imino group contained in _9 may be protected. ] Reaction with a compound having the formula R_1_4 group [wherein R_1_4 is a lower alkyl group or a substituted lower alkyl group [the substituent is a di-lower alkylamino group, an aryl group, Heterocyclyl group or formula -
COR_7 group [In the formula, R_7 is the same group as R_1_2 above, a hydroxyl group, or a formula ▲ Numerical formula, chemical formula, table, etc. ▼ group (In the formula, R_8
, R_9 and B have the same meanings as described above. ) is shown. ]. ]. ]; Reaction to convert a carboxy group to a lower alkoxycarbonyl group; Reaction to convert a nitro group to an amino group; Reaction to remove a protecting group for an amino group or imino group; and/or a compound (I a)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1, R_2 and dotted lines are included] The bond has the same meaning as described above, and R_3 is the formula -Q-A-COR_7
represents a group (in the formula, R_7, Q and A have the same meanings as described above), and R_4 and R_5 are the same or different and are a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group,
Halogen atom, hydroxyl group, lower alkoxy group, aliphatic acyloxy group, amino group, mono- or di-lower alkylamino group, aliphatic acylamino group, aliphatic acyl group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, ureido group, lower It represents an alkylureido group, a thioureido group, a lower alkylthioureido group, a cyano group, or a nitro group, and R_6 represents a hydrogen atom or a group similar to the above formula R_1_4. ] A method for producing a pyridazinone derivative and a pharmacologically acceptable salt thereof. (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R_3 is the formula -Q-A-COR_7 group [In the formula, Q
represents an oxygen atom or a sulfur atom, A represents an alkylene group, R_7 represents a hydroxyl group; a lower alkoxy group; an aryloxy group; an aralkyloxy group; represents a single bond or an imino group (-NH-), and R_8 and R_9 are the same or different and are a hydrogen atom, an alkyl group, an alkyl group having 1 or 2 substituents (the substituents include a halogen atom, a hydroxyl group, a lower Alkoxy group, aryloxy group, amino group, mono- or di-substituted amino group, carboxy group, lower alkoxycarbonyl group, cycloalkyl group, heterocyclyl group,
Indicates an aryl group or a heteroaryl group. ), cycloalkyl group, aryl group or heteroaryl group. Alternatively, R_8 and R_9 together with the nitrogen atom to which they are attached represent a heterocyclyl group. Furthermore, the amino group and imino group contained in R_8 and/or R_9 may be protected. ]. ], R_4 and R_5 are the same or different and are hydrogen atom, lower alkyl group, halogeno-lower alkyl group, halogen atom, hydroxyl group, lower alkoxy group, aliphatic acyloxy group, amino group, mono- or di-lower alkylamino group, aliphatic group acylamino group, aliphatic acyl group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, ureido group,
Indicates a lower alkylureido group, a thioureido group, a lower alkylthioureido group, a cyano group, or a nitro group. ] Under acid catalyst, a compound having the general formula ▲Mathematical formula, chemical formula, table, etc.▼(VIII) It is reacted with a compound having a single bond or double bond), and then reacted with hydrazine to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ ( I b) (In the formula, R_1, R_2, R_3, (R_4, R_5 and the bond containing the dotted line have the same meaning as described above.), and if desired, the imino group of compound (Ib) is added with the formula R_1_
4 groups [wherein R_1_4 is a hydrogen atom, a lower alkyl group, or a substituted lower alkyl group [the substituent is a di-lower alkylamino group, an aryl group, a heterocyclyl group, or a group of the formula -COR]
_7 group (in the formula, R_7 has the same meaning as described above). ]. ] Reaction to introduce amino group, reaction to remove protecting group of imino group and/or compound ( I b
) is characterized by carrying out a reaction to convert the single bonds at the 4th and 5th positions into double bonds as appropriate ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R_1, R_2, R_3, The bonds including R_4, R_5 and dotted lines have the same meanings as above, and R_6
represents a hydrogen atom or a group similar to R_1_4 above. ) and a method for producing a pharmacologically acceptable salt thereof.